3-carboxylic acylamino-2, 4, 6-triiodo benzoic acids and the ethyl ester and nontoxic salts



Patented Sept. 23, 1952 3-CARBOXYLIC ACYLAMINO-2,4,6-TRIIODO BENZOICACIDS AND THE ETHYL' ESTER AND NONTOXIC SALTS Vernon H. Wallingford,Ferguson, Mo., assignor to Mallinckrodt Chemical Works, St. Louis, Mo.,a corporation of Missouri No Drawing. Application May 31, 1950, SerialNo. 165,355

11 Claims. 1

This invention relates to halogenated compounds and more particularly tonovel 3-acylamino-2,4,6-triiodobenzoic acids and their salts and esters.

This application is a continuation-in-part of my copending U. S. patentapplication, Serial No. 40,000, filed July 21, 1948.

Among the objects of this invention are the provision of new derivativesof benzoic acid which contain a plurality of iodine atoms; the provisionof compounds of the type indicated which are useful intermediates forthe preparation of other compounds of related structure; the provisionof compounds of the type referred to which possess relatively lowtoxicity toward human beings; the provision of compounds of the typereferred to which possess substantial solubility in water; the provisionof improved contrast media for X-ray diagnosis; the provision ofimproved X-ray contrast agents for urography or cholecystography; andthe provision of compounds which are relatively stable under normalconditions of storage and use and in the presence of body fluids. Otherfeatures will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the ingredients and combinations ofingredients, the proportions thereof, and features of composition whichwill be exemplified in the products hereinafter described, and the scopeof the application of which will be indicated in the following claims.

According to the present invention it has been found that aliphaticacylated 3-amino-2,4,6-triiodobenzoic acids possess many unexpected andvaluable properties. These compounds consist of the acids of the generalformula:

COOH

-NHacy1 l together with their salts and esters.

The compounds of this invention are of especial value as X-ray contrastagents, for which purpose many of them are preeminently suited. Somemembers of the series when injected intravenously in the form of asolution of one of their soluble pharmacologically acceptable salts, arerapidly concentrated in the kidneys and excreted in the urine, and whenadministered orally, are absorbed only slowly if at all from thegastrointestinal tract. Depending upon mode of administration, they maybe used'for visualization of the urinary system or the gastrorintestinal tract.

Others of these compounds are concentrated within the gall bladder,thereby rendering it opaque to X-rays. Even'though some of thesecompounds are more toxic than those used for urography, it has beenfound, nevertheless, that they are less toxic than other media ingeneral use for visualization of the'gall bladder. Thus as theproperties change, the field of usefulness also changes. Y

The compounds of this invention may be prepared from'3-amino-2,4,6-triiodobenzoic acid by the methods customarily employedfor acylating amine groups. The reaction medium may be either an excessof the acylating agent, or some other solvent maybe employed. Dioxanehas been found to be a particularly suitable solvent for many of thesereactions. When the acylating agent is an acid or acid anhydride, theyield and purity of the product may often be im-jproved by adding atrace of sulfuric acid as a catalyst to the reaction mixture. While notalways essential, the addition of a -catalyst appears to be beneficialin all such cases :The salts and esters of these compounds are preparedby the usual methods employed in preparing the salts and esters oforganic acids.

It has been found that many of the compounds of this invention mayadvantageously be purified by heating them with an' acid anhydrides'uchas acetic anhydride to form new anhydrides which crystallize easily fromacetic"anhyd ride'. Hydrolysis of the purified anhydride then gives thecorresponding acid in pure form. Instead of acetic anhydride, which ispreferredbecause' of its relative economy and availability, other loweraliphatic anhydrides may be employed.

The following examples illustrate the inven-v tion:

EXAMPLE 1 v 3-formylamino-2,4,6-triiodoben2oic acid A mixture of g. of3-amino-2,4,6-triiodo j benzoic acid [H Kretzer, Bericht e, 30, 1944(1897) Beilstein 14,'p. 414] with 300 ml. of formic acid (87%)containing 6 drops of concentrated sulfuric acid was stirred and heatedat -1041 C. After thirty, minutes approximately one-half of the originalsolid had dissolved. and a solid of.

into 1200 ml. of water and the solid was filtered off and washed withwater. After drying overnight at 95 C. the product weighed 53.3 g. andmelted with decomposition at 140-141" C. The product was recrystallizedby dissolving one part in a mixture of six parts of glacial acetic acidand four parts of dioxane, heating to 80 C. and then cooling to roomtemperature. The purified 3-formylamino-2,4,6-triiodobenzoic acid meltedwith decomposition at 250.8251.2 C. The equivalent weight was determinedto be 540 (theory 542.7) by titrating with standard alkali, usingphenolphthalein as an indicator.

EXAMPLE 2 3-acetylamino-2,4,6-triiodloben2oic acid3-amino-2,4,6-triiodobenzoic acid (51.5 g.) was mixed with 125 ml. ofacetic anhydride containing 2 drops of concentrated sulfuric acid andrefluxed for thirty minutes. The mixture was allowed to cool slightly,and then was poured into 600 ml, of water at room temperature andstirred until crystallization was complete. The mixed anhydride of3-acetylamino-2,4,6-triiodobenzoic acid with acetic acid thus preparedwas then separated by filtration and washed with water. Without drying,the solid was suspended in 600 ml. of water and hydrolyzed with a slightexcess of ammonium hydroxide. It was necessary to warm the mixtureslightly and stir it for about onehalf hour in order to dissolve all thesolid. The

solution was then treated with activated carbon, filtered andprecipitated with an excess of hydrochloric acid, filtered, washed anddried at 70 C. The yield Was 51.5 g. of3-acetylamino-2,4,6-triiodobenzoic acid which melted at 276.6-278.2 C.with decomposition when placed in the melting block at 260 C. and heatedat the rate of 3 C. .per minute. Due to decomposition, the melting pointvaries from about 269-280 C., depending upon the rate of heating andother conditions. The equivalent weight was 565 (theory 557). Analysisshowed: 19.77, 19.60% carbon; 1.59, 1.42% hydrogen. Calculated forCeHeOsNIs. 19.4%carbon; 1.08% hydrogen.

EXAMPLE 3 3-acetyZammo-2,4,6-triiodobenzoic acidvacetylamino-2,d,6-triiodobenzoic acid. The solid 7 was collected on afilter, washed with acetic anhydride and. dissolvedin 1200 ml. of waterwith ammonium hydroxide. This solutionvwas then made acid to litmus withacetic acid,'bleached with 10 g. of sodium bisulfite, treated with 10 g.of activated carbon and filtered. A gleaming, chalk-white solid wasobtained by adding 1:2 diluted hydrochloric acid to the stirred,'hot(55-:

65 C.) solution. The 3 -acetylamino-'2,4,6-triv iodob'enzoic acid waswashed, anddried at 70 C. The yield was 92.9 g, (83% of theory) of aprodnot which melted with decomposition beginning at 269 C. when placedin the meltingpoint apparatus at 260 C. An additional0l8 g. of product 4which melted at 268.5 C. was obtained by hydrolyzing the aceticanhydride mother liquor.

EXAMPLE 4 Sodium salt of 3-acetylamino 2,4,6-triiodobenzoic3-acetylamino-2,4,6-triiodobenzoic acid (28 g.) was dissolved in alittle over 50 m1. of l N sodium hydroxide in a round-bottom flask. ThepH was adjusted to slightly over 7 and the solution was evaporated on asteam bath under reduced pressure. After. the residue became solid, itwas further dried overnight in a Vacuum desiccator con-- taining calciumchloride. The salt Weighed 31.2 g., theory being 29.0 g., indicatingthat the product contains about 7% water of crystallization when driedunder these conditions. The finished salt was scraped from the flask andground.

10.0 g. of the anhydrous sodium salt are soluble in 11.5 ml. of water at25 C.

The sodium salt of 3-acetylamino-2,4,6-triiodobenzoic acid when injectedintravenously as an aqueous solution is rapidly concentrated in thekidneys and excreted in the urine and when administered orally isabsorbed only slowly if at all from the gastrointestinal tract.Depending upon the mode of administration, it may be used forvisualization of the kidneys, ureters, bladder, upper gastrointestinaltract or lower gastrointestinal tract.

EXAMPLE 5 3-propionyZamino-2,4,6-triiodobenzoic acid A suspension of50.0 g. of 3-amino-2,4,6-triiodobenzoic acid in ml. of propionicanhydride containing 3 drops of concentrated sulfuric acid was slowlyheated with good mechanical stirring. When the temperature reachedl20l25 C. the material began to dissolve and a clear, amberc'oloredsolution was obtained. This temperature was maintained for about onehour, and then the solution Was allowed to cool. The reaction mixturewas poured onto 500 ml. of water and sufiicient ammonium hydroxide wasadded to make the solution basic. The mixture was stirred well untilsubstantially all of the material haddissolved. It was then filtered anddiluted to;ab0ut 1000 ml. and acidified with concentrated hydrochloricacid. The precipitation was repeated. An 87 yield was obtained at thispoint,

Further purification was obtainedthrough the ammonium salt. The freeacid was dissolvedin ten times its weight of water and suificientammonia to make the solution basic. The addition of 10% of the totalweight of ammonium chloride precipitated the ammonium salt. This wasfiltered off, dissolved in about twenty times its weight of water, andfiltered. The addition of concentrated hydrochloric acid precipitatedthe free acid. The acid was filtered olf, washed well with water anddried in the air.

Anal. calcd. for C10HsO3NI3Z .I, 66.7; neut. equiv, 570.7. Found:I,.66.9; neut.-equiv., 571. g

7 EXAMPLE 6 3-butyryZamiaQ-ZAfi triiodobenzoic acid A mixture of 12.9 g.of 3-amino.-2,4,6-triiodobenzoic acid, 25 ml. of n-butyric anhydride,25ml. dioxane and one drop of concentrated sulfuric acid, was refluxed forone-half hour and allowed to stand. After three days no crystals hadformed. It was poured into-150 ml. of water and stirred one-half hour tohydrolyze the excess n-butyric anhydride. The water layer was decantedfrom the brown oily layer (the anhydride of3-butyrylamino-2,4,6-triiodobenzoic acid with n-butyric acid) and thelatter was washed again with an equal volume of water and decanted. Twohundred m1. more water were added, stirred and the oily layer dissolvedusing ammonium hydroxide. After makingthe solution acidto litmus withacetic acid, was treated with activated carbon and filtered. Thesolution was still brown. While heating at 70-80" C., hydrochloric acidwas added dropwise with stirring. A white precipitate formed,redissolved, then came out as a brown oil. The followin morning it wastarry-like. The liquid was poured off, replaced by 200 ml. of water andthe taffy dissolved with ammonium hydroxide. After warming to 55 C.,precipitation was again attempted with 10% hydrochloric acid. The oilreappeared. After adding 5 ml. of acetic acid, one gram of sodiumbisulfite and about 34 ml. of anhydrous denatured alcohol to the oilymixture, the resulting solutionwas treated with activated carbon andfiltered. A very :light brown solution resulted which was stirred andcooled to C. by adding ice, then precipitated very slowly with 3%hydrochloric acid. A light solid first separated which finallycrystallized to a yellow-white solid of a fine sandy consistency. It wasdried overnight in a vacuum desiccator. The product weighed 9.7 g. (66%of theory) and melted at 248 C. with decomposition. Found on analysis:22.57, 22.72% carbon; 2.02, 2.01% hydrogen. Calculated f or C11H10O3NI3!22.57% carbon; 1.72% hydrogen.

' EXAMPLE 7 3-caproyZamino-2,4,6-triiodobenzoic acid A suspension of103.0 g. of 3-amino-2,4,6- triiodobenzoic acid in 1100 ml. of boilingtoluene was prepared in a two liter flask equipped with stirrer andcondenser, and a portion of the toluene (250 ml.) was distilled off toremove any water. The condenser was then set for reflux and 40 ml. ofcaproyl chloride was added. In twelve minutes the solution was almostclear, but within the next three minutes a heavy precipitate formedwhich filled the liquid in the flask. Refluxing was continued forfortyfive minutes. At the end of that time, the mixture was too thick tostir. It was allowed to cool and then filtered.

The solid material was partially dissolved in 400 ml. of water andsufl'icient sodium hydroxide was added to make the mixture basic. Themixture was transferred to a separatory funnel and solution completed byadding a small amount of ether. The two layers were separated, thealkaline solution was again washed with ether, then filtered and heatedon the steam bath to remove the ether. It was diluted to 1500 ml. andacidified with hydrochloric acid. The3-caproylamino-2,4,6-triiodobenzoic acid material which precipitated wasfiltered, washed well with water and dried in the air.

One hundred and six grams of 3-caproylamino-2,4,6-triiodobenzoic acidwas recovered, representing a yield of 87%. The neutral equivalent was610. (Theory: 613.)

The reaction product was further purified by dissolving the acid in tentimes its weight of water and sufiicient ammonium hydroxide to, make thesolution basic. The ammonium Salt was,

salted out by the addition of ammonium chloride in the amount of 10% ofthe total weight of solu-* H a Ethyl3--acetylamino-2,4,6-triiodobenzocte, I

One hundred grams of 3-acetylamino-2,4,6 triodobenzoic acidwas mixedwith 200ml. of

anhydrous ethyl alcohol in a flask arranged with condenser forrefluxing.To the mixture was added sodium ethylate prepared by dissolving 4.15grams of sodium metal in ml. of af nhydrous ethyl alcohol. After adding400 grams of diethyl sulfate, the mixture was refluxed for eighteenhours. Itwas then poured into 1800 ml. of water andsodium bicarbonatewasadded until the mixture was no longer acid to litmus paper.

The solid ester was filtered ofi,.washed with water and dried. at 100?C. The mother liquor,

when acidified to Congo red with hydrochloric.

acid, yielded 22.3 grams of recovered '3-acetylamino-2,4,6triiodobenzoic acid. The dried ethyl 3 acetylamino 2,4,6 triiodobenzoateweighed, 78.1 grams which is a 97%yield based upon the starting materialactually consumed.

p The product was recrystallized from 5.0% ethyl alcohol by volume,using about 100 ml. for 5,

grams. After two crystallizations it melted at 207.2-208.0 C. I

Anal. calcd. for C11H1003NI32 C, 22.6; H, 1.7; I, 65.2. Found: C, 22.7;H, 1.9; I, 64.5.

Some of the many surprising and valuable properties possessed by thecompounds of the present invention are revealed in the following ab e:

Solubility i 1g Acid of Sodmm mgJkilo Salt g./l00 bod ml. water weiggtS-amino-ZA,fi-triiodobenzoic acid 9. 3 1, 2503formylam1no-2,4,6-triiodobenzoic ecid 71 8, 000 S-acetylamino2,4,6triiodobenzoic acid 94 10, 700 3-prop1onylammo-2,4,6-triiodobenzoicacid 37 8, 100 3-butyry1amino2,4,6-triiodobenzoic acid 60 4, 8003-caproylammo-2,4,6-triiodobenzoic acid 78 1, 450

The L. D. 50 value is the dosage necessary to kill 50% of the testanimals when the compound is injected intravenously as a solution of itssodium salt.

Not only doesacrylation in most cases increase the solubility and thetolerated doses many times relative to 3amino-2,4,6-triiodobenzoic acid,but the compounds of this invention compare favorably in these respectswith commonly employed but structurally dissimilar compounds containingsubstantially less iodine in their molecules.

The high solubility and low toxicity of these new compounds isunexpected, not only in view of the properties of the correspondingunacylated compounds but also because of the high 7 proportion of iodinewhich they contain. The compounds of this invention may containas muchas 68% iodine. Heretofore, it has been accepted that in general thetoxicity is directly related and the solubility inversely related to theproportion of iodine which is attached to an organic molecule. Thesolubility and toxicity relations of these compounds are exactly theopposite of what one would expect on the basis of 'a study of the art-It is not intended that the compounds of this invention be limited tourographic or cholecystographic media, as the properties of thesecompounds make them useful for many other purposes. They may, forexample, be administered orally in the form of solutions, suspensions,capsules, tablets, etc., for visualization of the gastrointestinaltract. In such cases it is not even essential that soluble salts beemployed. In some-oases it is desirable to employ an oil or otherorganic diluent as a medium, in which cases thesolubilitycharacteristics of the esters are desirable. Moreover, theusefulness of these compounds is not confined to visualization of humanorgans, since they are equally useful for X-rayf visualization of otherstructures which cannot conveniently be viewed directly. In additio'n;the acrylamino benzoic acids of this invention may be used in thepreparation of other iodinated derivatives useful per se or as-furtherintermediates.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As many changes could be made in the above products without departingfrom the scopeof the" invention, it is intended that all mattercontained in the above description shall be interpreted as illustrativeand not in a limitingsense.

I- claim: T l. A compound selected from the group consisting of a3-acylamino-2,4,6-triiodobenzoic of the general formula:

(I? OOH If I NHacyl where acyl represents a lower aliphatic carboxylicacyl radical, and the ethyl ester and nontoxic salts thereof.

2. An aliphatic 3-acylamino-2,4,6triiodobenzoic acid of the generalformula:

(30 OH 3 I -NHacyl where acyl, represents a lower aliphatic carboxylicacyl radical, and in which the acyl group. contains at least two carbonatoms.

3. Ar aliphatic 3-acylamino-2,4,6-triiodobenzoic acid of the generalformula:

where acyl represents a lower aliphatic carbqX-ylic acyl radical.

4. A non-toxic salt of an aliphatic 3-acylamino-2,4,6-triiodobenzoicacid of the general formula:

' coon R FERENCES CITED The following references are of record in thefile of this patent:

Wheeler et. 2.1., Chem. J., 42, 454. 1909). Kretzer, Berichte Deut.Chem. 30, 1944 (1897) "Goldberg et al., Chem. Abst., vol. 41, col. 41311.947).-

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 3-ACYLAMINO-2,4,6-TRIIODOBENZOIC ACID OF THE GENERAL FORMULA: 